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New Drug Lead Fights Bacteria that can be Lethal by Disrupting Quorum Sensing and Biofilms

27.01.2003

Compound could lead to a new generation of antibiotics that battle resistance

University at Buffalo scientists have discovered a promising new drug lead that works by inhibiting the sophisticated bacterial communication system called quorum sensing.

The new compound is active against Pseudomonas aeruginosa, the gram-negative infection that strikes -- and usually kills -- cystic fibrosis patients and many others whose immune systems are compromised. The bacteria, like many others that have been routinely treated by antibiotics, have developed strains that are antibiotic-resistant.

The compound and the method the UB scientists used to develop it are described in the current (January 25, 2003) issue of Chemistry & Biology. The research also is discussed in a second article in the "Previews" section of the journal.

A patent application has been filed on the method of synthesis and the compound.

"With this work, we have taken a critical step toward inhibiting quorum sensing for clinical applications," said Hiroaki Suga, Ph.D., UB associate professor of chemistry and corresponding author on the paper.

Quorum sensing is the process by which bacterial cells "sense" that their numbers have reached a certain level, Suga explained, so that they then can mount an effective attack. The process gets switched on, he said, in response to the autoinducers that accumulate in bacterial cells as they begin reproducing.

Once the cells "sense" that a quorum has been reached, they begin to communicate, a process that in turn "throws the switch" for manufacturing virulence factors, such as biofilms.

These tough, layered, polysaccharide shells provide the bacteria with a nearly impenetrable, self-protective mechanism that makes it extremely difficult, and in some cases impossible, to fight with antibiotics.

"Underneath the protective biofilm, the cells are happily reproducing, damaging the tissue and producing toxins," said Suga.

Based on the structure of the quorum-sensing molecule, the autoinducer, the UB team synthesized a library of compounds. This approach then allowed the scientists to discover a subset of molecules that, like the natural autoinducer, activate quorum sensing.

"We then synthesized a small, focused library of quorum-sensing agonists," said Suga. "Surprisingly, this focused library yielded a quorum-sensing antagonist."

"It has been shown that knockout of the quorum-sensing genes in P. aeruginosa significantly reduced its virulence, so this cell-to-cell communication process is an interesting new drug target," he said.

By disrupting the communication process, he explained, the new compound could lead to drugs that will prevent the formation of biofilms, restoring the potency of antibiotic treatments and limiting the development of antibiotic resistance.

Since many other bacterial infections operate through quorum sensing, this molecule likely will boost research into methods to disrupt those as well, he added.

In addition, he said, compounds that inhibit quorum-sensing function differently from traditional antibiotics by attenuating pathogenicity, and therefore could prove very effective against resistant strains.

Suga explained that the quorum-sensing system is responsible for regulating a number of genes, including those that control the production of virulence factors.

"We now have a synthetic molecule that inhibits the master regulatory gene of quorum sensing," he said.

While Pseudomonas aeruginosa, which is ubiquitous in hospitals, has no effect on healthy people, it can be lethal to patients whose immune systems are compromised. In addition to cystic fibrosis patients, whose lungs become clogged with the bacteria, it infects patients receiving chemotherapy, burn patients, AIDS patients, those on ventilators, with catheters and others.

"The resistance problem demands development of a new type of drug, which differs in concept from traditional antibiotics," said Suga.

"Our work demonstrates a new strategy for identifying and designing antagonists to quorum sensing," he said. "We hope that additional studies in this direction lead us to discover even more potent quorum-sensing antagonists, thus generating a new type of antibiotic drug."

The paper is co-authored by Kristina M. Smith, who works in Suga’s lab and is doctoral candidate in the UB Department of Biological Sciences in the College of Arts and Sciences, and Yigong Bu, a former doctoral candidate at UB, who earned his doctorate from the UB Department of Chemistry.

Funding for the work was provided by the Interdisciplinary Research and Creative Activities Fund, Office of the Vice President for Research at UB.

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